Iron deficiency is an extremely common cause of anemia. However, the pathophysiology of iron deficient anemia remains poorly understood. Unlike anemias associated with defects in globin or in porphyrin synthesis, iron deficiency anemia employs unique hematopoietic control mechanisms to prevent marrow erythroid hyperplasia and to increase platelet production. These control mechanisms most likely serve protective functions, preventing an erythroid drain on limited iron reserves and increasing hemostatic capability to limit hemorrhagic red cell loss.
Understanding hematopoietic control mechanisms in iron deficiency has clinical relevance for multiple reasons. For example, inappropriate function of these mechanisms interferes with the efficacy of erythropoietin treatment in patients with a variety of chronic anemias. Many of these patients are elderly individuals with debilitating anemias due to chronic renal failure, chronic inflammatory conditions, or malignancy. Erythropoietin provides an opportunity to ameliorate the anemia while avoiding the exposure risks of red cell transfusions. While iron supplementation may partially restore responsiveness, frequent problems may exist with either non-compliance in taking oral iron, poor intestinal absorption, inefficient marrow utilization of existing iron stores, iron overload, and risk of infection with associated with intravenous iron infusion. Thus, circumventing the hematopoietic control mechanisms in iron deficiency could offer a strategy for enhancement of erythropoietin efficacy. On the other hand, in patients with serious deficiencies of total body iron stores, inadvertent abrogation of this control mechanism could cause a lethal reallocation of iron away from vital cellular functions such as supporting mitochondrial oxidative phosphorylation. Knowing these control mechanisms may permit prospective identification of patients at risk for life-threatening drug reactions. Another clinical benefit may arise from harnessing these mechanisms for the treatment of neoplasia, in particular polycythemia vera. Rather than phlebotomy to induce iron deficiency, one could employ agonists designed to activate the hematopoietic control mechanisms in a more highly controlled manner, permitting rapid and effective modulation of the red cell mass. Finally, exciting new opportunities for manipulation of platelet production, either positively or negatively, will arise from understanding the mechanisms of iron-deficient thrombocytosis.
Accordingly, there is a need for compositions that overcome iron deficiency, diminish erythroid repression, and regulate platelet production. For example, there is a tremendous need for new approaches in boosting poor platelet recovery post chemotherapy, a common clinical problem for which no adequate treatments currently exist. Therefore, the methods and compositions of the current invention proffer such results through the use of isocitrate, isocitrate derivatives, citrate and other Krebs cycle metabolites, aconitase and aconitase inhibitors, and/or aconitase agonistic proteins, wherein the utilization of these compositions can provide a synergistic effect that leads to the manipulation of red blood cell and platelet production, depending upon the needs of the subject.